The present invention is novel hydroxamate analogs of acyl residues of selected nonsteroidal antiinflammatory drug(s) (NSAID(S)). Such NSAIDS include indomethacin and its analogs of U.S. Pat. No. 3,161,654; sulindac and its analogs of U.S. Pat. No. 3,654,349; tolmetin and its analogs of U.S. Pat. No. 3,752,826; and furofenac and its analogs of U.S. Pat. No. 4,029,811; fentiazac and its analogs of U.S. Pat. No. 3,476,766; clidanac and its analogs of U.S. Pat. No. 3,565,943; ketorolac of U.S. Pat. No. 4,089,969; oxepinac of British Patent No. 1,476,214; fenclorac of U.S. Pat. No. 3,864,384; lonazolac of U.S. Pat. No, 4,146,721; metiazinic acid of U.S. Pat. Nos. 3,455,917 and 3,424,748; clopirac of Belgian Patent No. 777,207; clometacine of British Patent No. 1,260,868; etodolac of U.S. 3,939,178; indoprofen of British Patent No. 1,344,663; piriprofen of U.S. Pat. No. 3,641,040; carprofen of U.S. Pat. No. 3,896,145; oxaprozin of U.S. Pat. No. 3,578,671; pranoprofen of U.S. Pat. No. 3,931,205; suprofen of U.S. Pat. No. 4,035,376; miroprofen of U.S. Pat. No. 3,978,071; tioxaprofen of U.S. Pat. No. 3,933,840; furaprofen of German Patent No. DE 3026402 or furobufen of U.S. Pat. No. 3,728,349 or diclofenac of U.S. Pat. No. 3,558,690; and bucloxic acid of U.S. Pat. No. 3,754,021.
The above patents are each incorporated by reference.
Anthranilic acid derivatives of a fenamic acid series are previously known to include the generic compounds of the British Patent No. 989,951 or formula ##STR1## wherein Ar is .alpha.,.alpha.,.alpha.-trifluoro-m-tolyl; 2,3-xylyl, or 2,6-dichloro-m-tolyl, also in U.S. Pat. No. 3,852,333.
Of these, disclosures for unsubstituted hydroxamic acid of the acetyl residue of indomethacin are found in U.S. Pat. No. 3,624,103 and diclofenac are found in U.S. Pat. Nos. 4,092,430 and 4,173,577. However, no teaching to further substituted hydroxamic acids of indomethacin and diclofenac having the activity of the present invention compounds is found.
Among related aminobenzhydroxamic acids also previously known are compounds of the formula ##STR2## wherein R' is a saturated fatty hydrocarbon radical; phenyl, phenylalkyl, wherein the rings are optionally substituted by lower alkyl or lower alkoxy; or an aromatic heterocyclic group. This disclosure is in Japanese Application 24578/67 filed Apr. 2, 1964 by the Takeda Chemical Industry Co., Ltd. as an o-aminobenzhydroxamic acid analgesic derivative having less toxicity and analgesic, anticatarrhic, and antifebrile activity. Other related disclosures include U.S. Pat. No. 4,029,815 to compounds of the formula ##STR3## wherein X.sub.5 is trifluoromethyl, difluoromethyl, or nitro, X.sub.4 is H, Br, Cl, or nitro, and Q may be NHOH. These compounds have utility as antidiarrheal agents.
Selected fenamic acid derivatives having an hydroxamic acid derived substituent are found in copending U.S. application Ser. No. 134725.
Cyclized o-aminobenzhydroxamic-O-methylether of the formula ##STR4## wherein R" is alkyl, aralkyl, or a basic side chain and R' is H, Cl, or Br; are disclosed by Wolf, E. and Kohl, H. in "Cyclisiarungareaktionen von am Aminostickstoff Substituierten o-Aminobenzhydroxamsaure-O-methylesteror," Ann. Chem. Liebigs, 1975, 1245-1251.
Wolf and Kohl also disclose an intermediate hydroxamic acid derivative from which the cyclized o-aminobenzhydroxamic-O-methylether are made. The intermediate is ##STR5## wherein R.sub.c, R.sub.e, and R.sub.d are as defined below.
Other cyclized o-aminobenzhydroxamic acids disclosed are ##STR6## wherein R.sub.a is CH.sub.2 CO.sub.2 C.sub.2 H.sub.5, C.sub.6 H.sub.3 Cl(p)NO.sub.2 (m) and suggesting that R.sub.a may also be SO.sub.2 C.sub.6 H.sub.4 CH.sub.3 (p); and ##STR7## wherein R.sub.b is H or phenyl; R.sub.c is H, CH.sub.2 C.sub.6 H.sub.5, C.sub.6 H.sub.4 Cl(p), CH.sub.2 C.sub.6 H.sub.4 Cl(p), C.sub.6 H.sub.5, or CH.sub.3 ; R.sub.e is H or NO.sub.2 ; and R.sub.d is H or Cl. However, Wolf and Kohl do not disclose activity for these cyclized compounds and, further, do not make obvious the present invention.
Broadly, hydroxamic acid derivatives of selected aryl ring systems are disclosed in European Application Publication No. 0 196 184 and 196 674 having surprisingly high potency particularly by inhalation, oral efficacy, and with a surprisingly long duration of action. However, these aryl ring systems are in no way related to the present NSAID type compounds.
Two disclosures by Summers et al, (1) J. Med. Chem., 1987, 30, 574-80 and 2121-2126 and (2) In Vivo Characterization of Hydroxamic Acid Inhibitors of 5-Lipoxygenase disclosed at a Poster session at a National ACS meeting (New Orleaans) meeting in September, 1987 (Abstract) disclose hydroxamic acids as inhibitors of 5-lipoxygenase, however, the disclosures do not extend beyond very limited representative examples not including any derivatives having the selected acyl residues of the present invention.
Thus, the present invention are to selected novel derivatives of NSAIDS and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions for treating allergy, psoriasis, inflammation, arthritis, pain, pyrrhia, and the methods for such treatment.